US8420644B2 - Pharmaceutical composition intended for the prevention or for the treatment of cerebral oedemas - Google Patents

Pharmaceutical composition intended for the prevention or for the treatment of cerebral oedemas Download PDF

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US8420644B2
US8420644B2 US11/446,256 US44625606A US8420644B2 US 8420644 B2 US8420644 B2 US 8420644B2 US 44625606 A US44625606 A US 44625606A US 8420644 B2 US8420644 B2 US 8420644B2
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day
compound
formula
tet
moclobemide
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US20060276472A1 (en
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Marie-Emmanuelle Le Guern
Philippe Girard
Jean-Marie Gillardin
Laurence Berthon-Cedille
Bernard Hublot
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Biocodex SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to a pharmaceutical composition intended for the prevention or for the treatment of cerebral edema.
  • Cerebral edema is characterised as being an excessive accumulation of water in the intra- and/or extracellular compartments of the brain (Pollay (1996) In Neurosurgery, 2 nd ed. Mc Graw Hill Book Co., New York, 335-344). Cerebral edema may be of neurological origin, as in the cases of ischaemic attacks, intracerebral haemorrhages, brain tumours, cases of meningitis or of encephalitis, or of non-neurological origin, as in cases of diabetic ketoacidosis, lactic acidosis, hypertensive encephalopathy, malignant hypertension, hyponatraemia or an effect of high altitude.
  • cerebral edema The principal consequence of cerebral edema is an increase in the intracranial fluid pressure, leading to a reduction in the blood supply to the brain and the partial or total destruction of insufficiently vascularized cerebral tissues.
  • Moclobemide is a benzamide derivative which inhibits type A monoamine oxidase in a reversible manner and which is currently used as an antidepressant. Few undesirable side effects following its use are documented.
  • the object of the present invention is to provide novel compounds which do not have the drawbacks of the compounds which are already known, within the framework of the prevention or of the treatment of cerebral edema.
  • the present invention derives from the discovery by the inventors that moclobemide allows the prevention or the treatment of cerebral edema.
  • Cerebral edemas is used to denote the conditions in which there is an excessive accumulation of water in the intra- and/or extracellular compartments of the brain. Cerebral edemas are described in particular in Pollay (1996) In Neurosurgery, 2 nd ed. Mc Graw Hill Book Co., New York, 335-344.
  • the compounds of formula (I) above are capable of acting, in particular by inhibiting type A monoamine oxidase, according to a process different from that implemented by the compounds usually used within the framework of the treatment of cerebral edema and therefore do not have their detrimental effects.
  • NR 1 represents a heterocycle selected from the list comprising:
  • n 2 and the alkyl chain —(CH 2 ) n — is not substituted.
  • the invention also relates to the use as defined above of a compound of formula (I) represented by the following formula (II):
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined above, with the proviso that at least one of R 2 , R 3 , R 4 , R 5 and R 6 represents a halogen atom.
  • the invention also relates to the use as defined above of a compound of formula (I) represented by moclobemide, of the following formula (III):
  • the cerebral edema is following a cerebral vascular accident, a cerebral trauma, a cerebral tumour, cerebral metastases of a cancer, a cerebral abscess, a hypertensive attack, a diabetic ketoacidosis or a neuropaludism.
  • the medicament is suitable for administration to an individual requiring a unitary dose thereof of approximately 5 mg to approximately 900 mg, in particular approximately 150 mg to approximately 450 mg of the compound of formula (I).
  • the medicament is suitable for administration to an individual requiring a dose thereof of approximately 5 mg/day to approximately 900 mg/day, in particular approximately 150 mg/day to approximately 450 mg/day of the compound of formula (I).
  • the medicament is suitable for oral, intravenous, intramuscular or rectal administration.
  • the medicament is presented in the form of tablets, capsules, powder, sachets, suppositories, sugar-coated pills, syrups, suspensions or solutions.
  • the compound of formula (I) is associated with at least one additional compound intended for the prevention or for the treatment of cerebral edema, such as a compound selected from the list comprising a corticoid, in particular a glucocorticoid, glycerol, mannitol, a diuretic, in particular furosemide, a barbiturate, tetracosactide, an antibiotic, CDP-choline (cytidine 5′-diphosphocholine), vinpocetine, a calcium inhibitor and an NMDA (N-methyl-D-aspartate) antagonist.
  • a corticoid in particular a glucocorticoid, glycerol, mannitol
  • a diuretic in particular furosemide
  • a barbiturate tetracosactide
  • an antibiotic CDP-choline (cytidine 5′-diphosphocholine), vinpocetine, a calcium inhibitor and an NMDA (N
  • association of a compound of formula (I) with an additional compound indicated in the treatment of cerebral edema makes it possible to reduce the dose or the duration of administration of the said additional compound and thus to limit the side effects thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising by way of active substance at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and at least one additional compound intended for the prevention or for the treatment of cerebral edema, such as a compound selected from the list comprising a corticoid, in particular a glucocorticoid, glycerol, mannitol, a diuretic, in particular furosemide, a barbiturate, tetracosactide, an antibiotic, CDP-choline, vinpocetine, a calcium inhibitor, an NMDA antagonist, in association with a pharmaceutically acceptable vehicle.
  • a corticoid in particular a glucocorticoid, glycerol, mannitol
  • a diuretic in particular furosemide
  • a barbiturate tetracosactide
  • an antibiotic CDP-choline
  • vinpocetine a
  • the present invention also relates to products containing:
  • FIGS. 1A and 1B show the effect of moclobemide (Moc) on the cerebral edema induced by triethyltin (TET) in the rat, measured by the percentage of water in the brain (y axis).
  • the rats are distributed in groups of 10 individuals and are treated over 5 days (from day 0 to day 4).
  • FIG. 1A the rats receive neither TET nor moclobemide ( ⁇ ; ⁇ ), TET in the absence of moclobemide (+; ⁇ ), moclobemide at the rate of 50 mg/kg 2 times per day in the absence of TET ( ⁇ ; +), or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 50 mg/kg 2 times per day (+; +).
  • FIG. 1B the rats receive neither TET nor moclobemide ( ⁇ ; ⁇ ), TET in the absence of moclobemide (+; ⁇ ), moclobemide at the rate of 100 mg/kg 2 times per day in the absence of TET ( ⁇ ; +) or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 100 mg/kg 2 times per day (+; +).
  • the star symbol (*) shows a significant difference with respect to the groups without treatment (p ⁇ 0.05, ANOVA).
  • FIGS. 2A and 2B show the effect of moclobemide on the development of the body weight disrupted by triethyltin in the rat (y axis, in grams) as a function of time (x axis, in days).
  • the rats are distributed in groups of 10 individuals and are treated over 5 days (from day 0 to day 4).
  • FIG. 2A the rats receive neither TET nor moclobemide (circles), TET in the absence of moclobemide (squares), moclobemide at the rate of 50 mg/kg 2 times per day in the absence of TET (triangles), or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 50 mg/kg 2 times per day (diamonds).
  • FIG. 2B the rats receive neither TET nor moclobemide (circles), TET in the absence of moclobemide (squares), moclobemide at the rate of 100 mg/kg 2 times per day in the absence of TET (triangles) or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 100 mg/kg 2 times per day (diamonds).
  • the star symbol (*) represents a significant difference with respect the respective control groups (p ⁇ 0.05, ANOVA).
  • FIGS. 3A and 3B show the effect of moclobemide on the neurological index disrupted by triethyltin in the rat (y axis) as a function of time (x axis, in days).
  • the rats are distributed in groups of 10 individuals and are treated over 5 days (from day 0 to day 4).
  • FIG. 3A the rats receive neither TET nor moclobemide (circles), TET in the absence of moclobemide (squares), moclobemide at the rate of 50 mg/kg 2 times per day in the absence of TET (triangles), or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 50 mg/kg 2 times per day (diamonds).
  • FIG. 3B the rats receive neither TET nor moclobemide (circles), TET in the absence of moclobemide (squares), moclobemide at the rate of 100 mg/kg 2 times per day in the absence of TET (triangles) or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 100 mg/kg 2 times per day (diamonds).
  • the star symbol (*) represents a significant difference with respect to the respective control groups (p ⁇ 0.05, ANOVA).
  • FIGS. 4A , 4 B and 4 C show respectively the effect of moclobemide on the total ( FIG. 4A ), horizontal ( FIG. 4B ) or vertical ( FIG. 4C ) ambulatory activity (y axis, arbitrary units) disrupted by triethyltin in the rat, three days before any treatment (day ⁇ 3) or 5 days after the start of the treatment (day 4).
  • the rats are distributed in groups of 10 individuals and are treated over 5 days (from day 0 to day 4).
  • the rats receive neither TET nor moclobemide (white column), TET in the absence of moclobemide (black column), moclobemide at the rate of 50 mg/kg 2 times per day in the absence of TET (vertically hatched column), or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 50 mg/kg 2 times per day (diagonally hatched column).
  • the star symbol (*) represents a significant difference with respect to the respective control groups (p ⁇ 0.05, ANOVA).
  • FIGS. 5A , 5 B and 5 C show respectively the effect of moclobemide on the total ( FIG. 5A ), horizontal ( FIG. 5B ) or vertical ( FIG. 5C ) ambulatory activity (y axis, arbitrary units) disrupted by triethyltin in the rat, three days before any treatment (day ⁇ 3) or 5 days after the start of the treatment (day 4).
  • the rats are distributed in groups of 10 individuals and are treated over 5 days (from day 0 to day 4).
  • the rats receive neither TET nor moclobemide (white column), TET in the absence of moclobemide (black column), moclobemide at the rate of 100 mg/kg 2 times per day in the absence of TET (vertically hatched column), or TET (3 mg/kg/day) in the presence of moclobemide at the rate of 100 mg/kg 2 times per day (diagonally hatched column).
  • the star symbol (*) represents a significant difference with respect to the respective control groups (p ⁇ 0.05, ANOVA).
  • the inventors have demonstrated a protection of the moclobemide on cerebral edema induced by triethyltin (TET) chloride. Moreover, the effect of moclobemide has also been studied on the disruptions induced by TET for the 3 following parameters: weight development, neurological index and ambulatory activity.
  • TET triethyltin
  • Cerebral edema induced triethyltin (TET) chloride in the rat is a physiopathological model for the study of substances recommended in the treatment of certain cerebrovascular ailments (Linee et al., 1984 Ann. Pharm. Fr. 42, 431-442). Intoxication with TET is also a useful toxicological tool for testing products which act at the cerebral level in the elderly person for testing new products in senescence (Bentue-Ferer et al., 1985 Exp. Aging Res. 11, 137-141)
  • Cerebral edema due to TET is a chronic edema, appearing progressively and spontaneously reversible on condition that the intoxication is stopped. This edema develops exclusively at the level of the brain and of the spinal cord. Cerebral edema is characterised by an increase in the contents of water, sodium and chlorides without significant modification of the potassium content. The edema is reflected in a specific attack on the white matter (Naruse et al., 1982 J. Neurosurg. 56, 747-752), with a widening of the intramyelinic spaces and attack on the myelin (Kirschner and Sapirstein, 1982 J. Neurocytol. 11, 559-569).
  • the myelin of the central nervous system has the potential to recover its integrity after edematous damage by the withdrawal of the accumulated fluid (Yanagisawa et al., 1990 Neurochem. Res. 15, 483-486).
  • the scale of the edema which is accompanied by a weight loss and peripheral neurological disorders, is proportional to the dose of TET.
  • the substances to be tested are administered during the intoxication with tin and their activities are measured after 5 days.
  • certain cerebrovascular medicaments are active, such as dihydroergotoxin, ( ⁇ )eburnamonine and vincamine (Linee et al., 1984 Ann. Pharm. Fr. 42, 431-442).
  • the motor activity is detected with the aid of 15 photoelectric cells distributed over the walls of the rectangular compartment (320 ⁇ 290 ⁇ 100 mm) of the Opto-Varimex system from Colombus Instruments U.S.A.
  • the number of displacements (ambulatory activities, horizontally and vertically) of the animal is counted for 15 minutes.
  • the activity is expressed in arbitrary units: 1 unit corresponds to a passage in front of a photoelectric cell.
  • the triethyltin bromide at 97% (Sigma, ref 288047) is diluted in distilled water.
  • the moclobemide (Biocodex) is placed in suspension in Tween 80 at 1% (0.5 ml/100 g).
  • the statistical test utilised is the analysis of variance. When the result does not depend upon chance (to 5%), the groups treated which differ from the control group are determined.
  • TET administration of TET at 2 mg/kg/day orally has little effect at the level of the development of the body weight of the rats, and at the level of neurological index.
  • TET TET
  • TET TET
  • TET at 3 mg/kg/day, for 5 days leads to a significant increase in the percentage of water, from 79.75% and 79.65% respectively for the two control groups, to 81.40% and 81.26% respectively for the two groups treated, indicating the presence of a cerebral edema.
  • TET leads to a significant drop in weight at day 4 (Table 2 and FIGS. 2A , 2 B).
  • TET at 3 mg/kg/day, for 5 days leads to a significant increase in the neurological index from day 3, with a much stronger effect at day 4, indicating substantial neurological troubles.
  • moclobemide also inhibits the effect of TET.
  • TET at 3 mg/kg/day, for 5 days leads to a great decrease in the ambulatory activities at day 4, with and almost total inhibition of the vertical ambulatory activity.
  • TET Moclobemide Neurologicalindex (means ⁇ esm) (mg/kg/day) (mg/kg/day) day ⁇ 3 day 0 day 1 day 2 day 3 day 4 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 1.45 ⁇ 0.12* 3* 0 2 ⁇ 50 0 0 0 0 0.10 ⁇ 0.10 0 3 2 ⁇ 50 0 0 0 0.10 ⁇ 0.10 0.45 ⁇ 0.12* 1.25 ⁇ 0.25* 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0.90 ⁇ 0.15* 2.40 ⁇ 0.22* 0 2 ⁇ 100 0 0 0 0 0 0 3 2 ⁇ 100 0 0 0 0 0.25 ⁇ 0.15* 0.85 ⁇ 0.18* Neurological index: 0 ⁇ no apparent anomaly 1 ⁇ loss of spontaneous activity:

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US11/446,256 2005-06-06 2006-06-05 Pharmaceutical composition intended for the prevention or for the treatment of cerebral oedemas Active US8420644B2 (en)

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FR0505691 2005-06-06
FR0505691A FR2886549B1 (fr) 2005-06-06 2005-06-06 Composition pharmaceutique destinee a la prevention ou au traitement des oedemes cerebraux

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EP (1) EP1731156B1 (de)
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DE (1) DE602006002776D1 (de)
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210754A (en) * 1977-02-01 1980-07-01 Hoffmann-La Roche Inc. Morpholino containing benzamides
US5204327A (en) * 1988-11-18 1993-04-20 Ashi Kasei Kogyo Kabushiki Kaisha Treatment of cerebral edema with anp pharmaceutical compositions
US5792799A (en) * 1996-10-10 1998-08-11 Athena Neurosciences, Inc. Parenteral delivery of MAO A inhibitors
US6011019A (en) * 1996-03-12 2000-01-04 University Of South Florida Vasoactive effects and free radical generation by β-amyloid peptides
US6316504B1 (en) * 1993-10-18 2001-11-13 Technion Research And Development Foundation, Ltd. Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof
US20020072509A1 (en) * 2000-10-11 2002-06-13 Stein Donald Gerald Methods for the treatment of a traumatic central nervous system injury

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210754A (en) * 1977-02-01 1980-07-01 Hoffmann-La Roche Inc. Morpholino containing benzamides
US5204327A (en) * 1988-11-18 1993-04-20 Ashi Kasei Kogyo Kabushiki Kaisha Treatment of cerebral edema with anp pharmaceutical compositions
US6316504B1 (en) * 1993-10-18 2001-11-13 Technion Research And Development Foundation, Ltd. Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof
US6011019A (en) * 1996-03-12 2000-01-04 University Of South Florida Vasoactive effects and free radical generation by β-amyloid peptides
US5792799A (en) * 1996-10-10 1998-08-11 Athena Neurosciences, Inc. Parenteral delivery of MAO A inhibitors
US20020072509A1 (en) * 2000-10-11 2002-06-13 Stein Donald Gerald Methods for the treatment of a traumatic central nervous system injury

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Bonnet et al., "Moclobemide reduces intracellular pH and neuronal activity of CA3 neurons in guinea-pig hippocampal slices-implication for its neuroprotective properties." Neuropharmacology 2000:39;2067-74. *
Database Biosis 'online': Biosciences Information Services, Phila., Pa; Jul. 2000, Weinstock et al. development of a novel neuroprotective drug, (TV3326) for the treatment of Alzheimer's disease, with cholinesterase . . . , Drug Development Research, vol. 50, No. 3-4.
Gorgulu et al., "Reduction of Edema and Infarction by Mamntine and MK-801 After Focal Cerebral Ischaemia and reperfusion in Rat." Acta Neurochir (Wien) 2000: 142;1287-1292. *
Koch et al., "NMDA-antagonism (Memantine): An Alternative Pharmacological Therapeutic Principle in Alzheimer's and Vascular Dementia." Current Pharmaceutical Design (Jan. 2004): 10; 253-259. *
Priest, "Moclobemide: a range of opportunities." Psychopharmacology 1992: 106;S140-S141. *
Toth et al., "1-Oxa-3,8-diazospiro[4.5]decan-2-one derivatives with potent inhibitory effect on neural Ca-uptake and protecting action against TET-induced brain edema and memory and learning deficits." Eur J Med Chem 1997:32;27-38. *

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FR2886549A1 (fr) 2006-12-08
EP1731156B1 (de) 2008-09-17
US20060276472A1 (en) 2006-12-07
EP1731156A1 (de) 2006-12-13
DE602006002776D1 (de) 2008-10-30
FR2886549B1 (fr) 2007-09-07
ATE408409T1 (de) 2008-10-15
ES2314850T3 (es) 2009-03-16

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